1-substituted indenyl-3-aliphatic acids and esters

ABSTRACT

1-aralkylidene and aralkenylidene indenyl-3-aliphatic acids and their esters and amides are used as anti-inflammatory agents. They are prepared by the condensation of the corresponding 1indenone with an aralkyl or aralkenyl aldehyde under basic conditions.

United States Patent 1 3,622,623

[72] Inventors Tsung-Ying Shen [50] Field of Search 260/516, Westfield;470, 520, 473 F, 515, 469 Bruce 0. Linn, Somerville, both of NJ.

[21 1 App]. No. 75 5,798 [56] References Cited [22] Filed Aug. 28, 1968UNITED STATES PATENTS 1 1 Patented 23, 1971 3,274,240 9/1966 Fritz260/515 [73] Assignee Merck & Co., Inc. FOREIGN PATENTS Rahway, NJ.

633,314 12/1963 Belgium Primary Examiner-Charles B. Parker [54]l-SUBSTITUTED INDENYL-S-ALIPI-IATIC ACIDS Examiner Edward Jay GleimanAND FSTERS Attorneys-Harry E. Westlake, Jr., Michael C. Sudol, Jr. andI. 5 Claims, No Drawings Louis wolk [52] U.S. Cl 260/515,

424/285, 424/308, 424/309, 424/317, 424/324 [51] Int. Cl .l ..C07c145/00, C07c 147/06 ABSTRACT: I-aralkylidene and aralkenylideneindenyl-3- aliphatic acids and their esters and amides are used asanti-inflammatory agents. They are prepared by the condensation of thecorresponding l-indenone with an aralkyl or aralkenyl a1- dehyde underbasic conditions.

l-SUBSTITUTED lNDENYL-B-ALIPHATIC ACIDS AND ESTERS This inventionrelates to a new method of treating inflammation and to a preferredclass of new compounds of the indene series for such treatment. Morespecifically, it relates to the treatment of inflammation with a-(l-aralkylidene and aralkenylidene or heteroaralkylidene andheteroaralkenylidene-3-indenyl) lower aliphatic acids and their salts,amides and esters. More specifically also, it relates to the treatmentof inflammation with compounds of the formula: 1

C-C -M R I u II in which R may be aryl or heteroaryl;

X may be alkylene or alkenylene;

R may be hydrogen, alkyl, aralkyl, aryl, heteroaryl, halogen, hydroxy,alkoxy, haloalkyl, alkylthio and arylthio;

R may be hydrogen, lower alkyl, halogeno lower alkyl, fluorine, aminoacylamino, dialkylamino, N-morpholino, alkenyl, aralkylthio, hydroxy andalkoxy and together with R a methylene;

R is hydrogen or together with R a methylene;

R R, and R each may be hydrogen, alkyl, alkoxy, nitro, amino, acylamino,alkylamino, dialkylamino, dialkylaminoalkyl, sulfamyl, alkylthio,mercapto, alkyl-sulfonyl, arylsulfonyl, halogen, cyano, carboxyl,carbalkoxy, carbamido, aryl, halogenoalkyl, alkenyloxy, aralkyloxy,alkenyl, aryloxy, cycloalkyl and cycloalkyloxy, and

M may be hydroxy, lower alkoxy, substituted lower alkoxy, amino,alkylamino, dialkylamino, N-morpholino, hydroxyalkylamino,polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino, and thegroup OMe in which Me is a cation as well as the 2,3-dihydro derivativesof said compounds.

More specifically, also, in a separate and distinct aspect, thisinvention relates to a preferred new class of compounds especiallyuseful as anti-inflammatory agents, having the formula:

(EH i l R in which R, is aryl or heteroaryl, having at least onefunctional substituent;

X is an alkylene or alkenylene group;

R is alkyl, aralkyl, aryl, heteroaryl, halogen, hydroxy, alkoxy,haloalkyl, alkylthio and arylthio;

R is hydrogen, lower alkyl, halo lower alkyl, fluorine, amino,acylamino, dialkylamino, N-morpholino, alkenyl, aralkylthio, hydroxy,alkoxy and together with R;,' a methylene;

R is hydrogen or together with R, a methylene;

R is alkyl, alkoxy, nitro, amino, acylamino, alkylamino, dialkylamino,dialkylaminoalkyl, sulfamyl, alkylthio, mercapto, alkylsulfonyl,arylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, aryl,halogenoalkyl, alkenyloxy, aralkyloxy, alkenyl, aryloxy, cycloalkyl andcycloalkyloxy;

R and R are hydrogen or any of the groups defining R and M is hydroxy,lower alkoxy, substituted lower alkoxy, amino, alkylamino, dialkylamino,N-morpholino, hydroxyalkylamino, polyhydroxyalkylamino,dialkylaminoalkylamino, aminoalkylamino, and the group OMe, in which Meis a cation; as well as the 2,3-dihydro derivatives of said compounds.

The compounds of the above description, especially those of thepreferred class in which the aryl or heteroaryl group represented by Rhas at least one functional substituent and in which both R and R areother than hydrogen, possess a high degree of anti-inflammatoryactivity. They are highly active and are of value in the treatment ofarthritic and dermatological disorders and like conditions responsive toanti-inflammatory drugs. They also possess a useful degree ofantipyretic activity. More important, these compounds possess thesebeneficial activities with only a small fraction of the ulcerogenicsideeffect which is so characteristic of most antiinflammatory drugs. Theulcerogenic effect is found in these compounds to be greatly reduced andin many cases just about completely eliminated. These compounds can beadministered orally in capsules or may be applied topically orintravenously. The dosage in each case will depend on the specificcompound and the type and severity of the infection. For the presentcompounds, dosages of the order of 10 to 2000 mg. per day may be usedfor arthritic conditions, depending on the activity of the compound andthe reaction sensitivity of the patient.

The compounds used in the method of our invention are al-aralkylideneand aralkylenylidene or heteroaralkylidene andheteroaralkylenylidene-3-indenyl) aliphatic acids. Especially, they arecompounds of the formula given above. The substituents on the l-positionare aralkylidene or aralkylenylidene or heteroaralkylidene andheteroaralkylenylidene groups derived from aromatic or heterocyclicaromatic alkyl and alkenyl aldehydes. In the preferred class ofcompounds which fonn a separate aspect of this invention, the group X inthe above formulas is a lower alkyl or lower alkenyl group. Thealdehydes carry at least one functional substituent, preferably in thepara position. The term functional substituent" means one other thanhydrogen or alkyl, i.e., one whose polarity and general characteraffects the electron distribution in the aryl or hetero'aryl group,causing activation of some positions and/or inactivation of others. Onthe 2-position of the indene nucleus, one can place a number ofsubstituents such as alkyl, aralky, aryl, alkoxy, arylthio, nitro,amino, dialkylamino, etc. or the 2-position may be unsubstituted, inwhich case R becomes hydrogen. In the preferred class, which forms aseparate aspect of the invention, R, must be other than hydrogen.

Since these compounds are 3-indenyl aliphatic acids, the 3- positionmust have an aliphatic acid side chain with the indenyl nucleus on thealpha carbon of the aliphatic acid. Normally, one has an acetic orpropionic acid side chain, but other lower aliphatic acid side chainssuch as Bfifi-trifluoro-a-indenyl propionic acids, alkenoic acids andhigher alkanoic acids as well as other aliphatic acids such ascyclopropane carboxylic acids can be equally well used.

In addition, contemplated within the scope of this invention are3-indenyl glycines and N-alkyl-3-indenyl-glycines. In such compounds theacetic acid side chain carries in the a-position an amino ordialkylamino group. They are prepared by the reaction of hydroxylamineon the corresponding 3-indenylglyoxylate (from the 3-unsubstitutedindene and oxalyl chloride followed by esterification) and reduction ofthe oxime. The unsubstituted'a-amino group may be alkylated by any goodalkylating agent, such as dialkyl sulfate or alkyl halides.

The benzene ring of the indene nucleus may carry from one to threesubstituents of a number of types, preferably alkyl, alkoxy, halogen(such as fluoro or chloro) nitrogen and sulfur derivatives or variouscarboxylic acid functional derivatives or various carboxylic acidfunctional derivatives as enumerated above and described further below.In the case of the preferred compounds which form a separate aspect ofthis invention, there must be such a substituent. Preferably,

Preparation of a-(l-substituted-methylenyl-3-idenyl)'aliphathic acids I.-Praparation oi B-arylproplonic acid starting materials I (1) R5XCHCOOE R I CHO (|JH-CH-COOE R R0 OH I II III CH: C O O E CH=C- C O O EIV A) (5) Rs Bag CH-CH-COOE CHz-CHCOOH R v v1 i (6) R5 CH(COOE)2 R CHzXCHzC(COOE)z R VII VIII 5 IX Flow Sheet l (cont.) R

Equivalents X halogen, usually Cl or Br. R5 E esterifying group, usuallymethyl, ethyl or benzyl. R, H, alkyl, halogenated alkyl, aralkyl, aryland R0 heteroaryl. R R and R, H, alkyl, alkoxy, nitro. alkylthio,alkylsulfonyl, arylsulfonyl, halogenoalkyl, etc. as defined on page I,at least one not being H. Reagents R 1. Zn dush in anhydrous inertsolvent such as benzene and ether. R5 2. KHSO or p-toluene sulfonicacid. 3. NaOC H in anhydrous ethanol at room temperature. 4. Hpalladium-on-charcoal, 40 p.s.i. room temperature. 5. NaOH in aqueousalcohol at 20- 00. 6. NaOC,H or any other strong base such as NaH orK-tbutoxide. 7. Acid.

Flow Sheet ll (cont.) Equivalents X, E. R R and R, are same as flowsheet 1. R H, lower alkyl, halogenated lower alkyl. R aryl orheteroaryl. Reagents l. Friedel-Crafts Reaction using a Lewis Acidcatalyst, cf.

Organic Reactions, Vol. II, page 130. 2. Heat with polyphosphoric acid3. Reformatsky Reaction: Zn in inert solvent, heat. 4 p-Toulene sulfonicacid and CaCl or l at 200. 5. Wittig Reaction using c=0 f B I 0HR, CH-CH-COOH W CH VI X I XCHCOOE OH 4 l a CH-COOE CCOOE l m R0 XI XIIICH-COOE XII R!-X-i. iH

CH-COOE R; l I

XIV

80 in ether or benzene.

6. Reaction with aldehyde or ketone, using strong base as catalyst(K-t-butoxide or any alkoxide. NaOH, KOl-l, NaNl-l etc.), warming, ifnecessary, to form the carbanion in solvents such as liquid ammonia,dimethylformamide, l,2-dimethoxyethane, pyridine and aqueous alcohol,the 5-position of the indene should be substituted. Not only the freeacids, but the esters, amides and salts are included within the scope ofthis invention.

In the preparation of the compounds used in the method of thisinvention, the starting material is a B-aryl propionic acid. This isprepared according to the scheme shown in flow sheet I. Note that R,,, Rand R in this flow sheet do not have as extensive a definition as in thedefinition of the compounds included in our invention. The reason forthis is that it is very easy to make a large number of these othersubstituted indenes from the nitro indenes. In the preparation describedin flow sheet I, several alternative routes can be used. Thus, asubstituted benzaldehyde may be condensed with a substituted aceticester in a Claisen reaction or with an ahalogeno propionic ester in aReformatsky Reaction. The resulting unsaturated ester is reduced andhydrolyzed to give the benzyl propionic acid starting material.Alternatively, a substituted malonic ester in a typical malonic estersynthesis and acid hydrolysis of the resulting substituted ester yieldsthe benzyl propionic acid directly. This latter method is especiallypreferable for nitro and alkylthio substituents on the benzene ring.

In the preparation of the compounds used in this invention, again anumber of routes are possible, as shown in flow sheet ll. The first stepis the ring closure of the fi-aryl propionic acid to form an indanonewhich may be carried out by a Friedel- Crafts Reaction using a Lewisacid catalyst (Cf. Organic Reactions, Vol. 2, p. I) or by heating withpolyphosphoric acid. The indanone may be condensed with an a-halo esterin the Reformatsky Reaction to introduce the aliphatic acid side chainby replacing the carboxyl group. Alternatively, this introduction can becarried out by the use of a Wittig Reaction in which the reagent isa-triphenylphosphinyl ester, a reagent which replaces the carbonyl witha double bond to a carbon. This is then immediately rearranged into theindene. If the Reformatsky Reaction route is used, the intermediate 3-hydroxy-3-aliphatic acid derivative must be dehydrated to the indene.The introduction of the l-substituent is carried out by direct reactionof the indene with the aldehyde of the struc' tural characteristicsdefined, using a strong base as a catalyst and warming, if necessary, tofonn the carbanion. A variety of other bases such as sodium hydroxide,potassium hydroxide, sodamide, quaternary ammonium hydroxides and thelike may be used. The reaction can be carried out in a number ofsolvents such as polar solvents like dimethoxyethane, aqueous methanol,pyridine, liquid ammonia, dimethylformamide and the like or even innonpolar solvents such as benzene, etc. This reaction is described inflow sheet ll. Note the E in the third state and in the 5th stage is alower alkoxy group and thus forms a lower alkyl ester of the desiredcompound. This can then be hydrolyzed to give the free acids from whichthe salts, other esters and the amides may be formed. Steps 6, 7 and 8of flow sheet ll can also be carried out when E is hydrogen.

In the introduction of the l-substituent by the method described in flowsheet ll, any aryl or heteroaryl alkyl and alkenyl aldehyde may be useddirectly in the base condensation.

Among the aldehydes which may be used are cinnamaldehyde,hydrocinnamaldehyde, a-tolualdehyde, substituted cinnamaldehydes,hydrocinnamaldehydes and a-tolualdehydes and heteroacetaldehydes,heteropropenals and heteropropanals. Various aldehydes include such asZ-methoxycinnamaldehyde 4-methoxycinnamaldehyde3,4-dimethoxycinnamaldehyde 4-methylcinnamaldehydeZ-nitrocin'namaldehyde 3-nitrocinnamaldehyde 4-nitrocinnamaldehyde4-dimethylaminocinnamaldehyde 2-chlorocinnamaldehyde4-chlorocinnamaldehyde 2,4-dichlorocinnamaldehyde 4-bromocinnamaldehyde4-methylthiocinnamaldehyde 4-methylsulfinylcinnamaldehyde4-methylsulfonylcinnamaldehyde 4-chloro-a-methylcinnamaldehyde4-chloro-2-nitrocinnamaldehyde 4-chloro-3-nitrocinnamaldehyde4-nitro-a-methylcinnamaldehyde 4-nitro-B-methylcinnamaldehyde4-nitro-B-phenylcinnamaldehyde a-methylcinnamaldehydeB-ethylcinnamaldehyde a,B-dimethylcinnamaldehydea-cyclopentylcinnamaldehyde 3,4-methylenedioxycinnamaldehyde3,4,5-trimethoxycinnamaldehyde 4-methoxyhydrocinnamaldehyde 4-secbutylhydrocinnamaldehyde 4-nitrohydrocinnamaldehyde4-chlorohydrocinnamaldehyde 4-methylthiohydrocinnamaldehyde4-nitro-a-methylhydrocinnamaldehyde 4-nitro-B-methylhydrocinnamaldehyde4-chloro-a-methylhydrocinnamaldehyde4-chloro-B-methylhydrocinnamaldehyde a-methylhydrocinnamaldehydeB-methylhydrocinnamaldehyde a,a-dimethylhydrocinnamaldehyde4-chloro-a-tolualdehyde 4-methoxy-a-tolualdehyde4-methylthio-a-tolualdehyde a-methyl-a-tolualdehydea-ethyl-a-tolualdehyde 4-nitro-a-methyl-a-tolualdehyde4-chloro-a-methyl-a-tolualdehyde 2'-thienylacetaldehyde B-( 2 -thienyl)propenal B-( 2 '-thienyl )propanal 3'-pyridylacetaldehyde4'-pyridylacetaldehyde 2'-pyridylacetaldehyde 2-furylacetaldehyde5'-chloro-2'-thienylacetaldehyde a-naphthylacetaldehydeB-naphthylacetaldehyde B-(a'-naphthyl)propenal B-( 3 -pyridyl )propenalB-(4'-pyridyl)propenal B-(2'-furyl)propanal B-( 2'-pyridyl )propanal B-(a-naphthyl )propanal B-(2'-quinolyl)propanal B-( 2 '-pyrrolidinyl)propanal B-(2-benzofuranyl)propanal B-(2-quinolyl)propenal B-( 2'-py'rrolidinyl )propenal B-( 2'-naphthyl)propenal Bfi-diphenylpropen'al2'-indanacetaldehyde The aldehydes used in this invention are known orcan easily be prepared by the Rosenmund reduction of the availablecorresponding acid halides. Appropriately desired end products havingvarious substituents on the l-aryl or hetero ring can be prepared byusing suitable reactions in order to convert one group to another. Thesubstituents on the aromatic rings are preferably in the 4-position.

The products of this invention can contain geometric isomers, and areincluded as a part of this invention. In those products with one doublebond at C-l both the cis" and trans forms may be produced during thealdehyde condensation. For those products with two double bonds, such asthe cinnamylidene products, four isomeric forms may exist. Two of thefour forms may be selectively prepared by employing the aldehyde ofappropriate configuration, such as trans cinnamaldehyde. A preferredisomer may then be separated by conventional methods such aschromatography. Chemical and photo isomerization techniques may also beused.

Although the syntheses described produces esters of the acids of thisinvention, some desired esters are more easily obtained by forming asimple ester of the final acid, hydrolyzing to the free acid andreesterifying. The simple lower alkyl or benzyl esters are usually theones used in the syrlthesis of the compounds. Other esters are moredesirable from the standpoint of therapeutic utility of the compounds,such as the methoxymethyl, diethylaminoethyl, dimethylaminoethyl,dimethylaminopropyl, diethylaminopropyl, N-pyrrolidinylethyl,N-piperidinylethyl, N-pyrrolidinylmethyl, N-methyl-2-pyrrolidinylmethyl, N-morpholinylethyl, N-ethyl-Z-piperidinylethyl, 4-methyl-l-piperazinylethyl, methoxyethoxyethyl, andthe like. These are mostly prepared from the corresponding alcohol andthe indenyl acid. 7

The amides, both the simple amide and the substituted amides, aresimilarly prepared from the indenyl acids and the corresponding amines.Especially useful therapeutically are the morpholide, thebishydroxyethylamide and the like.

Similarly, salts are obtained by neutralizing the indenyl acids withbases or by metathesis of other salts. Especially useful are themetallic salts such as the alkali metal or alkaline earth salts and theamine and quaternary ammonium salts, which are water soluble, but theheavy metal salts such as iron, aluminum, etc. are also usable for somepurposes.

As has been pointed out above, it is preferable in the preparation ofmany types of the compounds of this invention, to use a nitrosubstituent on the benzene ring of the indanone nucleus and convert itlater to a desired substituent since by this route a great manysubstituents can be reached. This is done by reduction of the nitro tothe amino group followed by use of the Sandmeyer Reaction to introducechlorine. bromine, cyano or xanthate in place of the amino. From thecyano derivatives hydrolysis yields the carboxamide and carboxylic acid;other derivatives of the carboxy group such as the esters can then beprepared. The xanthates, by hydrolysis, yield the mercapto group whichmay be oxidized readily to the sulfonic acid or alkylated to analkylthio group which can then be oxidized to alkylsulfmyl andalkylsulfonyl groups. These reactions may be carried out either beforeor after the introduction of the l-substituent.

The procedure of flow sheet [I is especially advantageous whensubstituents other than alkyl groups are to be on the 2- position of theindene ring system. Such substituents as phenyl, benzyl, alkoxy,arylthio such as phenylthio, alkylthio such as methylthio and ethylthioand nitro are best introduced by constructing the proper indanone andreplacing the keto group by the desired aliphatic acid side chain.

Many of the indanones useable in flow sheet ll are known in theliterature and are thus readily available as intermediates for the restof the synthesis. Among the compounds of this type which are known areS-methoxy indanone 6-rnethoxyindanone -methoxyindanone6-methyl-2-benzylindanone S-metylindanone 5-methyl-6-methoxyindanone5-methyl-7-chloroindanone 4-methoxy-7-chloroindanone4-isopropyl-2,7-dimethylindanone S-nitroindanone 7-nitroindanone7-phenylindanone 2-phenylindanone 6,7-benzoindanone5,6,7-trichloroindanone S-benzyloxyindanone 2-n-butylindanoneS-methylthioindanone 5-methoxy-7-nitroindanone o-fluoroindanone5,6-difluoroindanone 4,6-difluoroindanone 5:fluoro-G-methoxyindanone pmThe following examples should be construed as illustrations of theinvention and not as limitations thereof:

EXAMPLE 1 6-Methoxy-2-Methylindanone In a 500 ml. 3-necked flask isplaced 36.2 g. (0.55 mole) of zinc dust and in a 250 ml. addition funnelis charged a solution of ml. anhydrous benzene, 20 ml. of anhydrousether, 80 g. (0.58 mole) of p-anisaldehyde and 98g. (0.55 mole) ofethyl- Z-bromo-propionate. About 10 ml. of the solution is added to thezinc dust with vigorous stirring and the mixture is warmed gently untilan exothermic reaction commences. The remaining reactants are addeddropwise at such a rate that the reaction mixture is refluxing smoothlyon its own accord (ca.

30-35 min.). After addition is completed, the mixture is placed in awater bath and refluxed for 30 minutes. After cooling to 0 C., 250 ml.of 10 percent sulfuric acid is added with vigorous stirring. The benzenelayer is extracted twice with 50 ml. portions of 5 percent sulfuric acidand washed twice with 50 ml. portions of water. The aqueous acidiclayers are combined and extracted with 2 X 50 ml. ether. The combinedetheral and benzene extracts are dried over sodium sulfate. Evaporationof solvent and fractionation of the residue through a 6-inch Vigreuxcolumn afl'ords 89 g. (69 percent) of the product,ethyl-2-hydroxy-2-(p-methoxyphenyl)-l-methylpropionate, b.p. l55-l65 C.1.5 mm.)

By the method described in Vander Zanden, Rec. trav. chim. 68, 413I949), the above compound is converted to 6- methoxy-2-methylindanone.

EXAMPLE 2 Ethyl-S-Methoxy-2-Methyl-3-lndenyl Acetate A solution of l3.4g. of 6-methoxy-2-methyl indanone and 21 g. of ethyl bromoacetate in 45ml. benzene is added over a period of 5 minutes to 21 g. of zinc amalgam(prepared according to Org. Syn. Coll. Vol. 3) in l 10 ml. benzene and40 ml. dry ether. A few crystals of iodine are added to start thereaction, and the reaction mixture is maintained at reflux temperature(ca. 65 C.) with external heating. At 3-hour intervals two batches of 10g. zinc amalgam and 10 g. bromoester are added and the mixture is thenrefluxed for 8 hours. After addition of 30 ml. of ethanol and ml. ofacetic acid, the mixture is poured into 700 ml. of lzl aqueous aceticacid. The organic layer is separated, and the aqueous layer is extractedtwice with ether. The combined organic layers are washed thoroughly withwater, ammonium hydroxide and water. Drying over sodium sulfate,evaporation of solvent in vacuo followed by pumping at 80 C. (bathtemp.) (k2 mm.) gives a crudeethyl-(l-hydroxy-2-methyl-6-methoxy-indenyl)acetate (ca. 18 g.).

A mixture of the above crude hydroxy ester, 20 g. of ptoluenesulfonicacid monohydrate and 20 g. of anhydrous calcium chloride in 250 ml.toluene is refluxed overnight. The solution is filtered and the solidresidue is washed with benzene. The combined benzene solution is washedwith water, sodium bicarbonate, water and the dried over sodium sulfate.After evaporation, the crude ethyl-5-methoxy-2- methyl-3-indenyl acetateis chromatographed on acid-washed alumina and the product is eluted withpetroleum ether-ether (v/v 50-100 percent) as a yellow oil (1 L8 g., 70percent).

EXAMPLE 3 6-Methoxy-Z-Methylindanonea-Methyl-B-(p-methoxyphenyl)propionic acid (15 g.) is

added to g. of polyphosphoric acid at 50 C. and the mixture is heated at83-90 C. for 2 hours. The syrup is poured into iced water, stirred forone-half hour and then extracted with ether three times. The ethanolsolution is washed with water twice and percent NaHCO five times untilall the acidic material has been removed. The remaining neutral solutionis washed with water and dried over sodium sulfate. Evaporation of thesolution gives 9.1 g. of the indanone as a pale yellow oil.

" EXAMPLE 4 a-Methyl-B-( p-Methylthiophenyl)Propionic Acid To a solutionof 2.3 g. (0.1 mole) of sodium in 100 ml. of absolute alcohol is added17.4 g. (0.1 mole) of diethyl methylmalonate and 17.3 g. (0.1 mole) ofpmethylthiobenzylchloride. The mixture is heated under reflux in a waterbath for 3 hours. The reaction mixture is poured into water and theaqueous solution is extracted six times with ether and dried. It is thenevaporated to yield diethyl methylp-methylthiobenzyl malonate. The crudeproduct is then saponified by heating with excess 4 percent sodiumhydroxide in aqueous ethanolic solution. The solution thus formed isconcentrated, extracted with ether to remove any neutral material, andacidified with dilute sulfuric acid. The acidic mixture is heated on asteam bath for 1 hour, cooled and then extracted with ether. Evaporationof the ether solution gives a-methyl-/3(p-methylthiophenyl)propionicacid.

EXAMPLE 5 Ethyl-3-Hydroxy-2-Methyl-5-Nitro-3-lndanylacetatc Theprocedure of Example 2 is followed using 2-methyl-6- nitro indanone inequivalent quantities in place of 6-methyl-2- methyl indanone usedtherein. After the mixture is condensed, 30 ml. of ethanol and 50 ml. ofacetic acid are added. The mixture is then poured into 700 ml. of water.Extraction with ether gives ethyl-3-hydroxy-2-methyl-5-nitro-3-indanylacetate.

EXAMPLE 6 i Ethyl-S-Dimethylamino-3-Hydroxy-2-Methyl-3-lndanylacetate Asolution of 0.05 mole of ethyl-3-hydroxy-2-methyl-5-nitro-3-indanylacetate, 0.2 mole of 38 percent aqueous formaldehyde and2 ml. of acetic acid in 100 ml. ethanol is reduced catalytically in thepresence of a percent Pd/C catalyst under 40 1b. p.s.i. hydrogenpresence at room temperature. The solution is filtered, evaporated andchromatographed on 300 g. of silica gel to give ethyl-5-dimethylamino-3-hydroxy-2-methyl3-indanyl acetate.

EXAMPLE 7 EXAMPLE 8 1-Cinnamylidenyl-S-Methoxy-2-Methyl-3 -lndenyl AcidAcetic of p-toluenesulfonic acid acid.

To a solution of 4.36 g. of 5-methoxy-2-methyl-3-indenyl then frommethanol-water to give pure l-cinnamylidenyl-S-methoxy-Z-methyl-3-indenyl acetic acid, (mp. 21 2-214 C.).

When an equimolar amount of the aldehydes of table 1 below are used inplace of cinnamaldehyde in the above procedure, then the correspondingl-substituted-S-methoxy-Z -methyl-3-indenyl acetic acid is obtained.

TABLE I a-tolualdehyde cinnamaldehyde hydrocinnamaldehyde2-methoxycinnamaldehyde 4-methoxycinnamaldehyde 4-ethoxycinnamaldehyde 3,4-dimethoxycinnamaldehyde 4-methylcinnamaldehyde4-t-butylcinnamaldehyde 2-nitrocinnamaldehyde 3-nitrocinnamaldehyde4-nitrocinnamaldehyde 4-dimethylaminocinnamaldehyde4-diethylaminocinnamaldehyde 2-chlorocinnamaldehyde4-chlorocinnamaldehyde 2,4-dichlorocinnamaldehyde 4-bromocinnamaldehyde4-methylthiocinnamaldehyde 4-methylsufinylcinnamaldehyde4-methylsulfonylcinnamaldehyde 4-chloro-a-methylcinnamaldehyde4-chloro-2-nitrocinnamaldehyde 4-chloro-3-nitrocinnamaldehyde5-chloro-Z-methylcinnamaldehyde 4-nitro-a-methylcinnamaldehyde4-nitro-Bmethylcinnamaldehyde 4-nitro-fi-phenylcinnamaldehydea-methylcinnamaldehyde a-ethylcinnamaldehyde B-methylcinnamaldehydeB-ethylcinnamaldehyde a,B-dimethylcinnamaldehyde a-pentylcinnamaldehydea-cyclopentylcinnamaldehyde 3 ,4-methylenedioxycinnamaldehyde 3,4.5-trimethoxycinnamaldehyde 3 ,4-dimethoxy-a-methylcinnamaldehyde4-isopropyl-a-methylcinnamaldehyde 4-methoxyhydrocinnamaldehydeZ-methylhydrocinnamaldehyde 4-methylhydrocinnamaldehyde 4-secbutylhydrocinnamaldehyde 4-nitrohydrocinnamaldehyde4-chlorohydrocinnamaldehyde 4-methylthiohydrocinnamaldehyde4-methylsulfinylhydrocinnamaldehyde 4-methylsulfonylhydrocinnamaldehyde4-nitro-a-methylhydrocinnamaldehyde 4-nitro-l3-methylhydrocinnamaldehyde4-chloro-a-methylhydrocinnamaldehyde4-chloro-B-methylhydrocinnamaldehyde a-methylhydrocinnamaldehydeB-methylhydrocinnamaldehyde a,a-dimethylhydrocinnamaldehyde4-chloro-a-tolualdehyde 4-methoxy-a-tolualdehyde4-methylthio-a-tolualdehyde a-methyl-a-tolualdehydea-ethyl-a-tolualdehyde 4-nitro-a-methyl-a-tolualdehyde4-chloro-a-methyl-a-tolualdehyde 4-phenylbutanal 4-pheny1-2-butenal2'-thienylacetaldehyde B-(2'-thienyl )propenal B-( 2'-thienyl )propanal3 -pyridylacetaldehyde 4'-pyridylacetaldehyde 2'-pyridylacetaldehyde2'-furylacetaldehyde 5 '-chloro-2 '-thienylacetaldehydea-naphthylacetaldel de B-naphthylacetaldehyde B-( 2'-furyl )propenal B-(2'-pyridyl )propenal B-(a'-naphthyl)propenal B-( 3'-pyridyl )propenalfl-( 4'-pyridyl)propenal B-( 2'-furyl )propanal B-( 2 '-pyridyl)propanalB-(a'maphthyl )propanal B-( 2-quinolyl )propanal B-( 2'-pyrrolidinyl)propanal /3-(2'-benzofuranyl)propana1 B-( 2'-quinolyl )propenal B-(2-pyrro1idinyl )propenal fi-( 2'-naphthyl )propenal B,B-diphenylpropenal2'-indanacetaldehyde B-( 2'-benzothiazole )propenal B-( 3'-nitro-2-thienyl )propenal B-( l -methyl-2'-pyrrolyl)propenal B-( 1-methyl-2'-pyridyl)propenal EXAMPLE 91-Cinnamylidene-5-Dimethylamino-Z-Methyl-3lndenyl Acetic Acid Toasolution of 2.5 g. of the ester from example 6 in 15 ml. of1,2-dimethoxyethane at C. is added 1.32 g. of cinnamaldehyde followed by1.1 g. of potassium t-butoxide. The reaction mixture is kept in theice-bath for 4 hours and then allowed to stand at room temperature for18 hours. The mixture is diluted with 15 ml. of ether and the potassiumsalt is filtered. The salt is dissolved in 30 m1. of water andneutralized with dilute hydrochloric acid to pH 6-6.5. The crude acidprecipitated is collected by filtration and chromatographed on a silicagel column, using ether-petroleum ether (v/v 50-100 percent) as eluentto give pure cinnamylidene-S- dimethylamino-2-methyl-3-indenyl aceticacid.

When an equimolar amount of the aldehydes of table 1, example 8 are usedin place of cinnamaldehyde in the above procedure then the corresponding1-substituteddimethylamine-2-methy1-3-indenyl acetic acid is obtained.

EXAMPLE l0 1-l-lydrocinnamylidene-5-Methoxy-2-Methyl-3-lndenylaccticAcid A solution of 1.98 g. (0.009 mole) of 5-methoxy-2-methyl-3-indenylacetic acid (mp 172 C.) from saponification of the correspondingethyl ester described above, in 25 ml. of 1,2- dimethoxyethane is addeddropwise to a suspension of sodamide (from 0.46 g. sodium) in 250 ml. ofliquid ammonia. The mixture is stirred for 20 minutes and then asolution of 1.3 g. of hydrocinnamaldehyde in 5 ml. of1,2-dimethoxyethane is added. After 3 hours, 1.24 g. of ammoniumchloride followed by 10 ml. of water is added to decompose the reactionmixture. The mixture is poured into water and extracted with ether. Theaqueous phase is acidified with hydrochloric acid to yield the product.Recrystallizaton from ethyl acetatepetroleum ether gives purel-hydrocinnamylidene-5-methoxy- 2-methyl-3-indenylacetic acid.

EXAMPLE 1 1 When an equimolar amount of the aldehyde of table I, example8 are used in place of hydrocinnamaldehyde in the procedure of example10, then the corresponding l-substituted5-methoxy-2-methyl-3-indenylacetic acid is obtained.

EXAMPLE 12 1-( Cinnamylidene )-5-l-lydroxy-2-Methyl-3-lndencyl AceticEXAMPLE l3 a-(5-Methoxy-2-Methyl-3-lndenyl )propionic Acid The procedureof example 2 is followed using ethyl abromopropionate in equivalentquantities in place of ethyl bromoacetate used therein. There isobtained ethyl a-(l hydroxy-6-methoxy-2-methyl-l-indanyl)propionate andit is then dehydrated to ethyl a-(5-methoxy-2-methyl-3-indenyl)-propionate in the same manner. The U. V. spectrum of the product shows Amax. 2210, 2610, 2930 and 3040. A. E% 709. 221, 1 15 and 107.

The above ester is saponified to give a-(S-methoxy-Z-methyl-3-indenyl)propionic acid, U.V. absorption: A max. 2210, 2625.2930, 3040. A, E% 795, 301,132 and 128.

EXAMPLE 14 a-( l-Cinnamylidene-S-Methoxy-Z-Methyl-3-lndenyl)- PropionicAcid To 1.0 g. of a-(5-methoxy-2-methyl-3-indenyl)-propionic acid in 4.5cc. of Call dried DME at 0 C. is added 0.528 g. (0.004 mole) ofcinnamaldehyde followed by 0.46 g. of potassium t-butoxide. The mixtureis kept at this temperature 3.5 hours, then allowed to stand at roomtemperature for 2 days.

The reaction mixture is poured into water, acidified with 2.5 N HCl, andextracted with ether. The ether solution is then extracted with 5%Na,CO;, solution. The carbonate solution is filtered. the acidified with2.5 N HCl, extracted with Et,0. The ether solution is washed with waterand dried over sodium sulfate. The ether solution is then filtered andthe oil converted to the methyl ester by refluxing 4.5 hours with cc.anhydrous methanol and 5 cc. concentrated H,SO The methanol solution isconcentrated to 20 cc. and poured into ether and water. The ether layeris washed with water, bicarbonate and carbonate solutions. water, anddried over Na SO The solution is filtered and 10 g. silica gel added andthe mixture concentrated to dryness on a rotary evaporator. This solidis placed on a column of 200 g. silica gel and eluted with 1:1benzene/Cl-lCl to give pure methyla-(cinnamylidene-5-methoxy-2-methyl-3-indenyl)-propionatc.

To this oil in 3.9 cc. EtOH is added 0.3 cc. 11.7 N NaOH and 0.3 cc. H0, and the mixture is stirred at room temperature under a nitrogenatmosphere for 18 hours. The saponification mixture yieldsa-(1-cinnamylidene-5-methoxy-2- methyl-3-indenyl )propionic acid.

EXAMPLE 15 a-[ l-Methylthiocinnamylidene)-2-Methyl-5-Methoxy-3-lndenyll-Propionic Acid To a solution of 0.5 g.(0.00192 mole) of ethyl-a-[ 2-methyl- 5-methoxy-3-indenyll-propionicacid and 0.695 g. (0.0039 mole) of p-methylthiocinnamaldehyde in 3 ml.of anhydrous pyridine is added 1.63 g. of a 40 percent solution ofbenzyltrimethylammonium hydroxide (Triton-B) in methanol. The resultingsolution is allowed to stir at room temperature overnight.

The mixture is poured into a mixture of ice and water. acidified in 2.5N HCl, and extracted with ether. The ether solution is then washed with2.5 N HCl, till washing acidifies (once), then with water till neutral.The ether layer is then extracted with Na CO solution. The Na COsolution is washed with ether, acidified and extracted with ether. Ethersolution is washed with water, dried over Na SO and concentrated invacuo to an oil.

EXAMPLE l6 l-Cinnamylidene-2-Methyl-5-Methoxy-3-lndenylacetmorpholide Amixture of l-cinnamylidene-2-methyl-5-methoxy-3-indenylacetic acid (0.01mole) and thionyl chloride (0.03 mole) in a dried flask, condenser anddrying tube setup is heated on the steam bath until evolution of gasceases. Excess thionyl chloride is then removed in vacuo, the residuetaken up in a slight excess of anhydrous ether and added slowly to avigorously stirred, ice-cooled solution by dry morpholine (0.035 mole)in 100 ml. of ether. The mixture is stirred overnight at roomtemperature, filtered, the morpholine hydrochloride washed with excessether, and the combined ether filtrates washed with 2 X 100 ml. water,dried over anhydrous sodium sulfate, filtered, and ether removed invacuo. Chromatography of the crude product on a silica-gel column, usingv/v 50-100 percent ether in petroleum ether as eluent gives the desiredmorpholide.

Similarly, when morpholine is replaced by an equivalent amount of thefollowing amines, the corresponding amides are obtained.

Dimethylamine Ethanolamine Benzylamine N,N-diethylethylenediamineBenzylglycinate Piperidine pyrrolidine N-MethylpiperazineN-Phenylpiperazine N-Hydroxyethylpiperazine Piperazine DiethylamineDiethanolamine Aniline p-Ethoxyaniline p-Chloroaniline p-Fluoroanilinep-Trifluoromethylaniline Butylamine Cyclohexylamine MethylamineD-Glucosamine Tetra-o-acetyl-d-glucosamine D-galactosylamineD-mannosylamine N,N-dimethyl-glycine amide N,N-dibutylglycine amideN-methyl-2-aminomethylpiperidine N-methyl-Z-aminomethylpyrrolidineB-ethoxyethylamine Di(B-ethoxyethyl)amine B-phenethylaminea-phenethylamine Dibenzylamine D-mannosamine When the variousl-substituted-2-methyl-5-methoxy-3-indenyl acetic acid are used in theabove procedure in place of l-cinnamyl-2-methyl-5-methoxy-3-indenylacetic acid then the corresponding amide is prepared.

EXAMPLE l7 Esters of l-Cinnamylidene-2-Methyl-5-Methoxy-3-lndenyl AceticAcid A. Simple Esters A mixture of 0.1 mole ofl-cinnamylidene-2-methyl-5- methoxy-3-indenyl acetic acid, 0.2 g. ofp-toluene sulfonic acid, ml. of absolute ethanol and 75 ml. of drybenzene is refluxed on a steam bath while slowly distilling the solvent.After 17 hours the residual solvent is removed under reduced pressure.The residue is slurried in aqueous sodium bicarbonate and then withwater until neutral. The resulting ethyl ester may be recrystallizedfrom organic solvents such as ethyl acetate, benzene and the like. Whenmethanol, propanol, tbutanol and benzyl alcohol are used instead of theethanol in the above procedure, there is obtained the correspondingmethyl, propyl, t-butyl and benzyl esters.

B. Alkoxyalkyl Esters Chloromethyl methyl ether (0.055 mole) is added toa suspension of l-cinnamylidene-2-methyl-5-methoxy-3-indenyl acetic acid(0.05 mole) and anhydrous potassium carbonate (0.15 mole) in 250 ml. ofanhydrous acetone. The mixture is allowed to stir overnight at roomtemperature. Diethyl ether is added (about 200 ml.) and the mixture isfiltered. The filtrate is washed once with l00 ml. of saturated sodiumbicarbonate solution and twice with 100 ml. of water and dried overanhydrous sodium sulfate. lt is then filtered and the solvent is removedin vacuo. The residue is chromatographed on 200 g. of acid-washedalumina, using ether-petroleum ether (varying from 10 to 60 percentether by volume) as the eluant, to givemethoxymethyl-l-cinnamylidene-Z-methyLS-methoxy-3-indenylacetate.

C. Dialkylamino-alkyl Esters A solution of 0.0054 mole ofN,N-dicyclohexylcarbodiimide in 6 ml. of anhydrous tetrahydrofuran isadded to a solution of l-cinnamyl-2-methyl-5-methoxy-3-indenylaceticacid (0.005 mole) and 2-diethylaminoethanol (0.0054 mole) in I? ml. ofanhydrous tetrahydrofuran. The mixture is stirred at ambienttemperature, overnight. The dicyclohexylurea is removed by filtrationand 2 ml. of glacial acetic acid is added to the filtrate. After themixture has stood for one hour. it is filtered and 200 ml. of ether isadded to the filtrate. The solution is then extracted three times with100 ml. of 2.5N HCI and the extracts are combined, washed twice with 100ml. of ether, ice-cooled, made slightly alkaline with concentrated NH OHand extracted three times with l00 ml. of ether. The ether extractsarecombined, washed l0 times with I00 ml. of water to remove traces ofstarting amine, dried over anhydrous potassium carbonate, filtered andevaporated in vacuo. The oily residue isB-diethylaminoethyl-l-cinnamylidene-2-methyl-5-methoxy-3-indenylacetate.

When 2-dimethylaminoethanol, 323 l-propanol, 3- diethylamino-l-propanol,N-B-hydroxyethylpiperidine, N-B- hydroxyethylpyrrolidine,N-hydroxymethylpyrrolidine, N- methyl-2-hydroxymethylpyrrolidine,N-ethyl-Z-hydroxymethylpiperidine, l-B-hydroxyethyl-4'-methyl-piperazineor N-B-hydroxyethyl morpholine is used in the above procedure in placeof ldicthyluminoethanol, the corresponding B- dimethylaminoethyl,y-dimethylaminopropyl, ydiethylaminopropyl, B-N-piperidinylethyl,B-N-pyrrolidinylethyl, N-pyrrolidinylmethyl, 2-( l'-methylpyrrolidinylethyl, 4-methyll -piperazinylethyl, N-ethyl-2-piperidinylethyl and N-morpholinylethyl esters are obtained. 32 D.Phenyll -cinnamylidenyI-2-Methyl-5-Methoxy-3-lndenylacetate A solutionof 0.0054 mole of N,N'-dicyclohexylcarbodiimide in 6 ml. of anhydroustetrahydrofuran is added to a solution ofl-cinnamylidenyl-2-methyl-5-methoxy-3-indenylacetic acid (0.005 mole)and phenol (0.0054 mole) in 17 ml. of anhydrous tetrahydrofuran. Themixture is shaken vigorously and allowed to sit, stoppered, at roomtemperature overnight.

After filtering off the N.N"dicyclohexylurea, 2 ml. of glacial aceticacid is added to the filtrate and the mixture allowed to stand 1 hour.After filtering, 200 ml. ether is added to the filtrate and the ethersolution washed with 2 X 100 ml. saturated sodium bicarbonate solutionand 3 X 100 ml. water and then dried over anhydrous sodium sulfate. Themixture is filtered, concentrated in vacuo to 25 ml. and chromatographedon a g. acid-washed alumina column using ether-petroleum ether (v/v10-60 percent) as eluent to give phenyl-l-cin- Vnamylindenyl-2-methyl-5-methoxy-3-indenylacetate.

Similarly, using 2-( 2-methoxyethoxy)-ethanol, glycol or N-acetyl-ethanolamine in place of phenol in the above procedure gives2-(2-methoxyethoxy)-ethyl-l-cinnamylidenyl-2-methyl-5-methoxy3-indenylacetate,B-hydroxyethyll EiiinarnylidenyI-Z-methyl-S-methoxy-3-indenylacetate and[3- acetamidoethyll -cinnamylidenyl-Z-methyl-S-methoxy-3-indenylacetate,respectively.

A mixture of 0.06 mole of sodium l-cinnamylidene-2-methyl-5-methoxy-3-indenyl acetate and 0.05 mole of trityl bromide in Iml. anhydrous benzene is refluxed with rapid stirring under nitrogen forhours. The hot reaction mixture is filtered and the filtrate isconcentrated in vacuo. The residual oil is recrystallized from methylethyl ketone to give trityl-lcinnamylidene-Z-methyl-5-metl1oxy-3-indenylacetate.

When any of the other 3-indenyl acids described in other examples areused in place of the above described acidin any of the abovepreparations, the corresponding esters are obtained.

EXAMPLE I 8 N-( l-cinnamylidene-2-Methyl-5-Methoxy-3Indenylacetyl)-Glycine A. Benzyl-N-( l-cinnamy1idene-2-methyl-5-Methoxy-3-IndenylAcetyl)-Glycinate The procedure of example 18 is followed usingbenzylamino acetate in place of the morpholine to produce the abovenamedcompound.

B. N-( l-p-Chlorocinnamylidene-2-Methyl5-Methoxy-3-lndenylacetyU-GlycineBenzyl-N-( l-cinnamylidene-2-methyl-5-methoxy3-in- Kdenylacetyl)glycinate (0.003 mole) in a mixture of 25 ml. of anhydrousethanol and 2.5 ml. of 1N sodium hydroxide is allowed to stand at roomtemperature for 18 hours. The solution is diluted with water andextracted with ether. The aqueous layer is acidified with dilutehydrochloric acid and the organic product is extracted with ethylacetate, washed with water and dried over sodium sulfate. Evaporation ofthe solution gives N-1-cinnamylidene-2-methyl-5-methoxy-3-indenylacetyl)- glycine.

When any of the other l-aralkylideneand aralkenylideneorheteroaralkylidene and heteroaralkenylidene-3 indenyl aliphatic acidsdescribed in the other examples of these specifications are used in theabove procedure in place of thel-cinnamylidene-2-methyl-5-methoxy-3-indenyl acetic acid, thecorresponding indenyl acyl glycine is obtained.

EXAMPLE l9 2-Methyl--Fluoroindanone-l A.Ethyl-4-Fluoro-a-Methylcinnamate Into a dry l-liter 3-neck round bottomflask equipped with stirring, thermometer and nitrogen inlet tube ischarged sodiurn hydride (0.384 mole). Ethyl propionate (1.45 mole) isadded, the temperature kept at ca. l0 C. with a dry-iceacetone bath.Absolute ethanol (0.48 ml.) is then added, followed by a mixture ofethylpropionate (0.78 mole) and p-flurorbenzaldehyde (0.322 mole) addedat such a rate that the temperature stays at l5-20 C. The mixture iscooled to the dry-ice-acetone bath replaced by an ice bath, and themixture stirred l hour. A solution of 29.2 ml. of glacial acetic acid in108 ml. water is added, the mixture stirred ca. 15 minutes, transferredto a separatory funnel, the layers separated, and the aqueous layerextracted with 2 X 54 ml. ether. The ether and organic layers arecombined, washed with 2 X 36 ml. water and 3 X 97 ml. [0 percent aqueouspotassium carbonate solution, dried over anhydrous potassium carbonate,filtered, and the solvent removed in vacuo. Distillation of the oilyresidue in vacuo gives ethyl-4-fiuoro-a-methylcinnamate, b.p. l25l 31:5-6 mm.

Similarly, the use of o-fluorobenzaldehyde, m-fluorobenazldehyde orp-trifiuoromethylbenzaldehyde in place of pfluorobenzaldehyde in theabove procedure gives ethyl-2- fluoro-a-methyl-cinnamate,ethyl-3-fiuoro-a-methylcinnamate, andethyl-4-trifluoromethyl-a-methyl-cinnamate, respectively.

B. 4-Fluoro-a-Methylcinnam ic Acid To a solution ofethyl-d-fluoro-a-methylcinnamate (0.01 mole) in 25 ml. of ethanol isadded a solution of potassium hydroxide (0.01 mole) in 5 ml. water andthe mixture stirred overnight at room temperature under a nitrogenatmosphere. Water (ca. ml.) is added, the aqueous mixture washed with 3X 100 ml. ether, ice-cooled and acidified with 2.5N hydrochloric acid,and extracted with 3 X I00 ml. ethyl acetate. The combined ethyl acetateextracts are washed with 2 X I00 ml. water, dried over anhydrous sodiumsulfate, filtered, and the solvent removed in vacuo leaving4-fiuoro-amethylcinnamic acid, m.p. l5 l-l 53 C. (from ethanol.

Similarly, using ethyl-2-fluoro-a-methylcinnamate, ethyl-3-fluoro-a-methylcinnamate, or ethyl-4-trifiuoromethyl-amethylcinnamate inplace of ethyl-4-fiuoro-a-methylcinnamate in the above procedure gives2-fluoro-a-methylcinnamic acid, 3-fluoro-a-methylcinnamic acid and4-trifluoromethyla-methylcinnamic acid, respectively.

C. 4-Fluoro-a-Methylhydrocinnamic Acid A solution of4-fiuoro-a-methylcinnamic acid (0.23 mole) in 800 ml. of anhydrousethanol is reduced at room temperature under a hydrogen pressure of 40p.s.i. in the presence of 2 g. 5 percent palladium on carbon. Afterfiltering, the ethanol is removed in vacuo, several 40 ml. portions ofbenzene added and distilled away to remove moisture, and the oilyresidue dried in vacuo leaving 4-fluoro-a-methylhydrocinnamic acid.

Similarly, reduction of 2-fluoro-a-methylcinnamic acid, 3-fluoro-a-methylcinnamic acid, and 4-trifluoromethyl-amethylcinnamic acidusing the above procedure gives the corresponding hydrocinnamic acidderivative.

D. Z-Methyl-o-Fluoroindanone-l The procedure of example 3 is followedusing 4-fluoro-amethylhydrocinnamic acid in place of the methylmethoxyphenyl propionic acid used there, to yield 2-methyl-6-fiuoroindanone-l Similarly, 4-0uoro-2-methylindanonel 5-fluoro-2-methylindanone-l, and 6-trifluoromethylindanone-l, are obtained via theabove procedure (followed by chromatography on an acid-washed aluminacolumn [v/v 1230] using etherpetroleum ether [v/v 0-60 percent for the5-fluoro-2- methylindanone-l) from 2-fluoro-a methylhydrocinnamic acid,3-fluoro-a-methylhydrocinnamic acid, and 4-trifiuoromethyl-a-methylhydrocinnamic acid, respectively.

EXAMPLE 20 Ethyl-2-Methyl5-Fluoro-3-lndenylacetate The procedure ofexample 2 is followed using 2-methyl-6- fiuoroindanone-l in place of6-methoxy-2-methylindanone. The product isethyl-2-methyl-5-fiuoro-3-indenylacetate.

Similarly, the use of 4-fluoro-Lmethylindanonel S-fluoro-Z-methyIindanone-l, or 6-trifluoromethyl-2-methylindanonel, in place of2-methyl-o-fluoroindanone-l in the above procedure givesethyl-2-methyl-7-fluoro-3-indenylacetate,ethyl-2-methyl-6-fiuoro-3-indenylacetate, and ethyI-Z-methyl-5-trifluor0methyl-3-iudenylacetate, respectively.

EXAMPLE 2l l-Cinnamylidene-2-Methyl-5-Fluoro-S-Indenyl Acetic Acid A.The procedure of example 8 is followed using ethyl-2-methyl-5-fluoro-3-indenylacetate in place of indenyl ester used thereinas starting material, to give l-cinnamylidene-Z-methyl-5-fluoro-3-indenyl acetic acid.

B. Similarly, the use of ethyl-2-methyl-6-fluoro-3-indenylacetate,ethyl-2-methyl-7-fluoro-3-indenylacetate, ethyl-2-methyl-5-trifiuoromethyl-3-indenylacetate, ethyl-Z-methyl-5,6-difluoro-3-indenylacetate, ethyl-2-methyl-5,7-difiuoro-3-indenylacetate or ethyI-Z-methyl-5-methoxy-6-fiuoro-3-indenylacetate inthe same procedure gives l-cinnarnylidene-Z- methyl-6-fluoro-3-indenylacetic acid, l-cinnamylidene-Z- methyl-7-fluoro-3-indenyl acetic acid,l-cinnamylidene-Z- methyl--trifluoromethyl-3-indenyl acetic acid,l-cinnamylideneZ-methyI-S,6-difluoro-3-indenyl acetic acid,l-cinnamylidene-Z-methyl-S,7-difluoro-3-indenyl acetic acid andlcinnamylidene-2-methyl-5-methoxy-6-fluoro-3-indenylacetic acid,respectively.

C. When the procedure of example 8 is followed as in part A, but usingin addition, p-methylthiocinnamaldehyde in place of cinnamaldehyde,there is obtained the corresponding l-(pmethylthiocinnamylidene)compound.

D. When the compounds from Part C above are oxidized, the correspondingp-methylsulfinyl and p-methylsulfonyl com pounds are prepared.

E. When the procedure of example 8 is followed as in part A, but usingin addition, the aldehydes of table 1, example 8 in place ofcinnamaldehyde, there is obtained the correspondingl-substituted-2-methyl-5-fluoro-3-indenyl acetic acid.

EXAMPLE 22 l-Cinnamylidene-2-Phenyl-5-Methoxy-3 lndenyl acetic acid Theprocedure of example 2 is followed using 2-phenyl-6- methoxy-indanone-lin place of 6-methoxy-2-methylindanone to giveethyl-2-phenyl-S-methoxy-B-indenyl acetate. When this is used in theprocedure of example 8, there is obtained 1-p-chlorobenzylidene-2-phenyl-5-methoxy-3-indenyl acetic acid. When2-phenylindanone-l is used as the starting material in place of2-phenyl-o-methoxyindanone, there is obtainedl-cinnamylidene-2-phenyl-3-indenyl acetic acid.

When 2-thienyl-o-methoxyindanone-l (prepared by Claisen condensation ofanisaldehyde on ethyl thienyl-Z-acetate, followed by catalytic reductionover palladium and ring closure with polyphosphon'c acid) is used in theabove procedure in place of the 2-phenyl--methoxyindanone-1, thecorresponding 2-thienyl compound is obtained.

EXAMPLE 23 l-cinnamylidene-Z-Benzyl-S-Methoxy-3-lndenyl Acetic Acid Theprocedure ofexample 19A is followed, using p-methoxybenzaldehyde as thereagent to obtain ethyl-4-methoxy-abenzylcinnamate. This compound isused in the procedure of example 198; the product therefrom is used inthe procedure of example 19C and the resulting product is then used inthe procedure of example 19D. The compound thus prepared is theintermediate 2-benzyl-6-methoxyindanone-l. When the known compound,a-benzylhydrocinnamic acid is used in the procedure of example l9D,there is obtained Z-benzylindanone-l.

The procedure of examples 20 and 21 is followed using the2-benzylindanones prepared above as the starting material. The compoundsthus obtained are l-cinnamylidene-2-benzyl- 5-methoxy-3-indenyl aceticacid and l-cinnamylidene-Z- benzyl-3-indenyl acetic acid.

EXAMPLE 24 2-Methoxy-4-Methyl-lndanone-l A solution of 0.05 mole of2-hydroxy-4-methylindanone and 0.055 mole of potassium t-butoxide in 250ml. dimethylformamide is treated with 0.06 mole of methyl iodide at roomtemperature for 18 hours. The reaction mixture is diluted with 700 ml.of water and extracted with ether (2 X 300 ml.). The ethereal solutionis dried over sodium sulfate, evaporated to a syrup, and chromatographedon 200 g. of acid-washed alumina using ether-n-hexane (v/v 20-50percent) as eluents to give 2-methoxy-4-methyl-indanonel.

EXAMPLE 2S l-Cinnamylidene-2-Methoxy-7-Methyl-3-Indenyl Acetic Acid A.Ethyl-( l-hydroxy-2-methoxy-4-methyl-indenyl-acetate When2-methoxy-4-indanone-l is used in example 2 in place of6-methoxy-2-methyl-indanone-l, there is obtained ethyl-(l-hydroxy-2-methoxy-7-methylindenyl)acetate.

B. Ethyl-2-Methoxy-7-Methyl-3-lndenyl Acetate To a solution of the abovehydroxy ester (0.05 mole) and pyridine (0.06 mole) in 200 ml. ether isadded dropwise with ice-cooling and stirring 0.055 mole of methylchlorosulfinate. After the addition is completed, the mixture is stirredat room temperature for 4 hours and filtered. The filtrate is washedwith 0.1N hydrochloric acid, with water and then with 5 percent sodiumbicarbonate. After drying over sodium sulfate, the solvent is evaporatedin vacuo, and the residue is pyrolyzed under nitrogen in the presence of0.5 ml. of quinoline at (oil bath temperature l60240 C. The pyrolysisproduct is redissolved in ether, washed with water and dried over sodiumsulfate. Evaporation of the solvent and chromatography of the residue on200 g. of acid-washed alumina, using ether-n-hexane (v/v 2060 percent)as eluent, gives ethyl-2-methoxy-7-methyl-3-indenyl acetate.

C. l-Cinnamylidenyl-Z-Methoxy-7-Methyl-3-lndenyl Acetic Acid When theabove indenyl ester is used in place of ethyl-(5-methoxy-Z-methyl-S-indenyl)acetate in example 8, there is obtainedl-cinnamylidene-2-methoxy-7-methyl-3-indenyl acetic acid.

D. l-Cinnamylidene-Z-Hydroxy-7-Methyl-lndenyl Acetic Acid The product ofpart C is used in the procedure of example 12 in place of thel-cinnamylidene-2-methyl-5-methoxy-3-indenyl acetic acid used therein,to form l-cinnamylidene-S- hydroxy-Z-methyl-3-indenyl acetic acid.

EXAMPLE 26 l-Cinnamylidene-S-Phenyl-3-lndenyl Acetic Acid The procedureof example l9C is followed, using p-phenylcinnamic acid in place of thea-methyl-4-tluorocinnamic acid used therein. The resulting hydrocinnamicacid is used in the procedure of example 3 to form o-phenylindanone-l.This compound is then used in the procedure of example 2 to produceethyl-6-phenyl-3-indenyl acetate. This ester is condensed withp-chlorobenzaldehyde in the procedure of example 8 to form the desiredl-cinnamylidene-5-phenyl-3-indenyl acetic acid.

When 7-phenylindanone-l is used in the procedure of example 2 and theproduct is condensed with cinnamaldehyde in the procedure of example 8,there is obtained l-cinnamylidene-4-phenyl-3-indenyl acetic acid.

EXAMPLE 27 A. l-Cinnamylidene-2-Phenylthio-3-lndenyl Acetic AcidFollowing the procedure of example 2, 2-phenyl-thio indanonel isconverted to ethyl-2-phenylthio-3-indenylacetate. This ester iscondensed with cinnamaldehyde in the procedure of example 8 to form thedesired l-cinnamylidene-Z-phenylthio-3-indenyl acetic acid. H.l-Cinnamylidene-Z-Methylthio-5-Methoxy-3-lndenyl Acetic Acid 7Z-Bromo-o-methoxyindanone (0..l mole) dissolved in 150 ml. dry methanolis added slowly, in an atmosphere of nitrogen, to a solution of sodiumthiomethoxide prepared from 2.5 g. sodium and lOO ml. dry methanolcontaining 0.1 mole of methylmercaptan. The solution is refluxed for 1hour, concentrated in vacuo, poured into water and then extracted withether. The ethereal solution is washed with water and dried over sodiumsulfate. Evaporation of the solvent followed by chromatography on 300 g.of acid-washed alumina, using ether-n-hexane (v/v 10-50 percent) aseluent, gives 2- methylthio-6-methoxy indanone.

Using the procedure of example 2 and 8, the above indanone is convertedsuccessively to ethyl-(5-methoxy)-2- methylthio-3-indenylacetate andl-cinnamylidene-S-methoxy- 2-methylthio-3-indenyl acetic acid.

EXAMPLE 28 l-Cinnamylidene-2,6-Dimethyl-3-lndenyl-a-Dimethylamino AceticAcid A. Ethyl-2,6-Dimethyl-3-lndenyl-a-Aminoacetate A mixture of 0 .0lmole of ethyl-2,6dimethyl-3-indenylglyoxalate (prepared from2,6-dimethyl-3-indenylglyoxate (prepared from 2,6-dimethylidene andoxalic ester by the procedure of Thiele Ber 33 85] (1900) hydroxylaminehydrochloride (0.026 mole), ethanol (20 ml.) and ml. of pyridine isheated on a steam bath under nitrogen for 3 hours. The mixture isconcentrated in vacuo to about l0 ml. and poured into 250 ml. of ice andwater. After the ice has melted, the organic material is collected,washed well with water until the odor of pyridine is gone, and dried.The product is dis- 1o solved in 25 ml. of ethanol and 0.03 mole ofglacial acetic acid is added. Zinc dust (0.012 mole) is added graduallyand the mixture is warmed gently until all the zinc is dissolved. Themixture is filtered and 50 ml. of 2.5N HCl is added. The aqueous phaseis washed twice with 50 ml. of chloroform, cooled and made slightlyalkaline with concentrated Nl-LOH. it is then extracted three times with50 ml. of chloroform. These extracts are combined, washed with [00 ml.of water twice and dried over K,CO,. The solution is filtered andconcen-- trated in vacuo to give ethyl-2,6-dimethyl-3-indenyl-a-amino 20acetate.

B. Ethyl-2,G-Dimethyl-3-Indenyl-a-Dimethylamino Acetate A solution ofethyl-2,6-dimethyl-3-indenyl-a-amino acetate (0.05 mole) andmethyliodide (0.15 mole) in I00 ml. acetone 30-room temperature for 1820-the presence of excess (0.2 mole) potassium carbonate. 3solution isfiltered, cor centrated in vacuo and poured into 300 ml. of ,water. Theproduct is extracted with ether, washed with water and dried over sodiumsulfate. The ethereal solution is evaporated to a syrup andchromatographed on 200 g. of neutral alumina, using etherpetroleum ether(b.p. -60") (v/v 20-l00 percent) as eluents to give ethyl-2,6-dimethyll-indenyl-a-dimethylamino acetate.

C. 1-Cinnamylidenyl-2,6-Dimethyl-3-lndenyl-a Dimethylamino Acetic AcidThe procedure of example 8 is followed using the aboveethyl-2,6-dimethyl-3-indenyl-a-dimethylaminoacetate in place of theindenyl ester used therein. The product isolated is then purified bychromatography on a bed of thin plates of 8 inches by 8 inches crosssection coated with silica gel, using -ethylacetate-l-propanol as theeluent, to producel-cinnamylidenyl-2,6-dimethyl-3-indenyl-a-dimethylaminoacetic acid.

EXAMPLE 29 A. Z-Methyl-S-Methoxyindene 1. To a mixture of 7.56 g. ofsodium borohydride and 200 ml. of isopropanol is added dropwise asolution of 0.2 mole of 2-methyl-6-methoxyindanone in 50 ml. isopropanolat room temperature over a period of one-half hour. The mixture is thenheated at the reflux temperature for 4-8 hours, the reduction beingfollowed by thin-layer chromatography. After cooling, the mixture ispoured into one liter of iced water and extracted with 3 X 150 ml. ofether. The ethereal solution is washed with water, dried over sodiumsulfate, and evaporated to give crude 2-methyl-6-methoxy-l-indanol.

2. The above indanol (0.05 mole) is dissolved in a mixture of 25 ml.ether and 4.4 g. (0.055 mole) of pyridine. The solution is cooled to 0C. and to this is added slowly 5.8 g. (0.05

mole) of methyl chlorosulfinate over a period of 20-25 minutes. Afterstirring at 0-5 C. for an additional 30-60 minutes the mixture is pouredinto iced-water and extracted with ether. The ethereal solution iswashed with 0.2N

hydrochloric acid, sodium bicarbonate, water and dried over iced-water.After extraction with ether to remove the byproducts, the aqueous layeris acidified to give methyl-2- methyl-5-methoxy-3-indenyl glyoxalate.

C. Ethyl-Z-Methyl-S-Methoxy-3-lndenyl a-Dimethyl Aminoacetate Theprocedure of example 28A and 28B is followed succesl-Cinnamylidene-2-methyl-5-methoxy-3-indenyl-a-methoxy acetic acid A.Methyl-5-methoxy-2-methyl-3-indenyl-a-hydroxylacetate To a solution ofmethyl-S-methoxy-Z-methyl-3-indenylglyoxalate (0.01 mole) in 50 ml.methanol is added portionwise 0.005 mole of sodium borohydride withice-cooling and stirring. After two hours at 0-5 and 4 hours at roomtemperature, the reaction mixture is poured into iced water containingan excess of acetic acid. The product is extracted with ether and theethereal solution is washed with water, dried over sodium sulfate andconcentrated in vacuo. The residue is chromatographed on a silica gelcolumn (200 g.) using etherpetroleum ether (v/v 50-100 percent) aseluent to give methyl-5-methoxy-2-methyl-3-indenyl-a-hydroxyacetate. B.Methyl-S-methoxy-Z-methyl-3-indenyl-a-tosyloxyacetate To a solution of0.02 mole of methyl-5-methoxy-2-methyl-3 -indenyl-a-hydroxyacetate inI00 ml. pyridine at 0-5" is added 0.025 mole of p-toluene-sulfonylchloride portionwise. The mixture is allowed to stand at 5l0 for l8hours and is then poured into iced water. The product is extracted withether, washed with dilute hydrochloric acid, sodium bicarbonate, waterand then dried over sodium sulfate. Evaporation of the solvent andchromatography of the residue on a column of 500 g. silica gel, usingbenzene-petroleum ether (v/v I0-50 percent) as eluent, gives the desiredsulfonate ester. C. Methyl-5-methoxy-2-methyl-3Jndenyl-a-methoxy-acetateA solution of 0.05 mole of methyl-5-methoxy-2-methyl-3-indenyl-a-tosyloxy acetate and 0.05 mole sodium methoxide in 300 ml.methanol is heated under reflux for 4-8 hours under nitrogen until thesolution becomes neutral. The mixture is concentrated in vacuo to ca.I00 ml., poured into water and extracted with ether. The etherealsolution is washed with water, dried over sodium sulfate and evaporatedto a residue. The residue is chromatographed on a column of 500 g. ofsilica gel using ether-petroleum ether (v/v 30-l00 percent) as eluent togive the produce, methyl-5-methoxy-2-methyl-3-indenyl-a-methoxyacetate.D. l-Cinnamylidene-2-methyl-5-methoxy-3 -indenyl-amethoxy acetic acidThe procedure of example 8 is followed, using the product of part C inplace of the indenyl ester used therein, to producel-cinnamylidene-2-methyl-5 ,a-dimethoxy-3-indenyl acetic acid. E.l-Cinnamylidene-2-methyl-5-methoxy-3-indenyl-a-hydroxy acetic acid Theprocedure of example 8 is followed using the product of example 30 A inplace of the ethyl-2-methyl-5-methoxy-3-indenylacetate and using twicethe mole usage of potassium-tbutoxide. The product obtained isl-cinnarnylidene-Z-methyl- 5-rnethoxy-3-indenyl-a-hydroxy acetic acid.

EXAMPLE 3 l l-Cinnamylidene-2-fluoro-3-indenyl acetic acid The procedureof example 2 is followed using Z-fluoroindanone in place of the indanoneused therein. The product is then used in the procedure of example 8 togive l-cinnamylidene-2-fluoro-3-indenylacetic acid.

EXAMPLE 32 Methyl--methoxy-2-methyl-3-indenyl-a-fluoro acetate A mixtureof potassium fluoride (0.1 mole) and methyl-5-methoxy-2-methyl-3-indenyl-a-tosyloxy acetate (0.05 mole) in 200 ml.dimethylformamide is heated under nitrogen at the reflux temperature for2-4 hours. The reaction mixture is cooled, poured into iced water andthen extracted with ether. The ethereal solution is washed with water,sodium bicarbonate and dried over sodium sulfate. Evaporation of thesolvent and chromatography of the residue on an acid-washed aluminacolumn (300 g.) using ether-petroleum ether (v/v 2050 percent) aseluent, gives the product, methyl-5-methoxy-2-methyl-3-indenyl-a-fluoro-acetate.

The above product is then used in the procedure of example 8 to givel-cinnamylidene-2-methyl-5-methoxy-3-indenyl-afluoroacetic acid.

EXAMPLE 33 l-Cinnamylidene-S-methoxy-Z-methyl-3-indenyl-amorpholinoacetic acid A solution of methyl-5-methoxy-2-methyl-S-indenyl-atosyloxyacetate (0.01 mole) and morpholine (0.03 mole) in 50 ml.1,2-dimethoxyethane is heated under reflux for 4-8 hours under nitrogen.The mixture is concentrated to one third volume, diluted with water andextracted with ether. The ethereal solution is washed with water anddried over sodium sulfate. Evaporation of the solution andchromatography of the residue on a column of 100 g. neutral aluminausing etherpetroleum ether (v/v 50-100 percent) as eluent, gives theproduct, methyl-5-methoxy-2-methyl-3-indenyl-a-morpholino acetate.

The above product is then used in the procedure of example 8 to givel-cinnamylidene-2-methyl-5methoxy-3-indenyl-amorpholino acetic acid.

EXAMPLE 34 a-[ l-Cinnamylidene-2-methyl-5-meth0xy-3-indenyl1-01-benzylthioacetic acid The procedure of example 33 is followed, using0.05 mole ofbenzylmercaptan in place of the 0.03 mole of morpholine inthe first step, to yield a-[l-cinnamylidene-2-methyl-S-methoxy-3-indenyl]-a-benzylthioacetic acid.

EXAMPLE 35 l-Cinnamylidene-Z-methyl-S-methoxy methylacetic acid Theprocedure of example 2 is followed using ehtyl-abromo-B-fluoropropionatein place of ethylbromo acetate to produceethyl-2-methyl-5-methoxy-B-indenyI-a-fluoromethyl acetate. This is thenused in the procedure of example 8 to producel-cinnamylidene-2-methyl-5-methoxy-afluoromethylacetic acid.

EXAMPLE 36 1-Cinnamylidene-Z-fluoromethyl-S-methoxy-3-indenyl aceticacid The procedure of example 1 is followed, usingethyl-abromo-fl-fluoropropionate in place of ethyl-2- bromopropionate togive 6-methoxy-Z-fluoro-methylindanone. This is then used in theprocedure of example 2 to give ethyl-Z-fluoromethyl-S-methoxy-3-indenylacetate which, when used in the procedure of example 8, givesl-cinnamylidene-Z-fluoromethyl-S-methoxy-3indenylacetic acid.

EXAMPLE 37 a-( l-Cinnamylidene-2,6-dimethyl-3-indenyl)glycine A.Ethyl-2,6-dimethy1-3-indenyl-a-acetamido acetate The product of example28 A is stirred in pyridine with an excess of acetic anhydride. Themixture is drowned in water and the product,ehtyl-2,6-dimethyl-3-indenyl-a-acetamido acetate, is extracted withether. The extracts are washed with dilute l-lCl and then to neutralwith water. The extract is dried over Na SO and evaporated.

B. l-Cinnamylidne-2,6-dimethyl-3-indenyl-a-acetamido acetic acid Theproduct of part A is used in the procedure of example 8 to yield theabove-named compound.

C. a-( l-Cinnamylidene-2,6-Dimethyl-3-indenyl)glycine The product ofpart B is heated on a steam bath in 2N NaOH solution for 6 hours. Themixture is cooled and neutralized to pH 6.5 with dilute HCl to yield theabove-named amino acid.

EXAMPLE 38 l-Cinnamylidene-Z-methyl-S-methoxy-3-indenyla-alkylaceticacid A. l-Cinnamylidene-Z-methyl-5-methoxy-3-indenylacetamide Theprocedure of example 16 is followed using an ether solution of ammoniain place of the morpholine, to yield the above amide.

B. acetonitrile A mixture of 10 g. of the amide from part A and 20 cc.of POCl; is heated at 90-l00 for 4-5 hours. The mixture is then pouredinto ice-water and extracted with l00 ml. of ether. The extract iswashed with sodium bicarbonate, dried over Na SO and evaporated, toyield the above nitrile.

C. l-Cinnamylidene-Z-methyl-S-methoxy-S-indenyl-a-allylacetonitrile Amixture of 0.0l mole of the nitrile from part B and 0.0] mole of NaNl-lin toluene (100 cc.) is stirred at room temperature. Allyl chloride (0.0l 5 mole) is added and the mixture is stirred for 3-4 hours. It is thenpoured into a large volume of water and extracted with ether. Theextract is dried and evaporated to dryness, to yield the a-allylnitrile.

D. l-Cinnamylidene-2-methyl-5-methoxy-3-indenyl-a-allylacetic acid.

The a-allyl nitrile from example 38 C is refluxed 8 hours in a largevolume 6 N sulfuric acid. The mixture is then cooled, diluted with 4 to5 volumes of water and extracted with ether.

l-CinnamyIidene-Z-methyl-5-methoxy-3-indenyl The extract is dried andevaporated to dryness to yield the aallylacetic acid.

EXAMPLE 39 EXAMPLE 40 A.l-Cinnamylidene-Z-methyl-5-nitro-3-indenylacetic acid The product ofexample 7 is used in the procedure of example 8 to producel-cinnamylidene-2-methyl-5-nitro-3-indenylacetic acid. B.l-Cinnamylidene-Z-methyl-5-amino-3-indenylacetic acid The product ofpart A (1 mole) is added gradually to a refluxing 10 percent solution ofsodium sulfide (sufiicient to provide over 10 mole proportion). Themixture is refluxed for several hours and cooled. It is then cautiouslyacidified until H 5 has ceased to evolve and the mixture is acid toCongo Red paper. The residue is filtered, washed neutral with water andslurried in dilute aqueous sodium bicarbonate solution. This slurry isfiltered and the filtrate is acidified. The precipitate,lcinnamylidene-Z-methyl--amino-3-indenylacetic acid, is iso lated byfiltration, washed and dried. C. l-Cinnamylidene-Z-methyl-S-acetylamino3-indenyl-acetic acid A mixture of 5 g. of the product of part B, 5 g.of acetic anhydride and 50 ml. of pyridine is heated to reflux until nosubstantial test for free amine can be obtained on an aliquot. Themixture is then evaporated to dryness in vacuo to yieldl-cinnamylidene-2-methyl-5-acetylamino-3-indenylacetic acid. When otheracid anhydrides such as propionic anhydride, butyric anhydride, or acidchlorides such as benzoyl chloride, are used in place of aceticanhydride, the corresponding 5- acylamino compound is obtained. D.l-Cinnamylidene2-methyl-5-methylamino-3-indenyl-acetic acid or4-cyclohexylbenzaldehyde is used in place of methylthiobenzaldehyde,there is obtained the corresponding EXAMPLE 42l-Cinnamylidene-2-methyl-5-allyloxy-3-indenylacetic acid A mixture of0.1 mole of l-cinnamylidene-Z-methyl-S- hydroxy-3-indenylacetic acid,500 ml. of acetone,0.2 mole of l(,CO and 0.15 mole of allyl chloride isrefluxed overnight. The mixture is then drowned in a large amount ofwater and after acidification, extracted with ether. The ether extractis A mixture of 0.1 mole of the product of part C, 0.l mole of sodiumhydride and 100 ml. of dimethylformamide is stirred at room temperaturewhile 0.15 mole of methyliodide is added. The mixture is stirred untilthe reaction is substantially complete and then is added to 200 ml. ofcold water. After excess NaOH solution is added, the mixture is refluxeduntil deacylation is substantially complete. Acidification of themixture gives a precipitate of l-cinnamylidene-2-methyl-5-methylamino-3-indenylacetic acid. E.l-Cinnamylidene-2-methyl-5-cyano-3-indenylacetic acid The product ofexample 40 B is dissolved in 20 times its weight of 5 N HCl and slightlyover 1 mole proportion of sodium nitrite is added gradually at 0-5 C.The mixture is then stirred until diazotization is complete. The mixtureis then poured, with stirring, into a slurry of cuprous cyanide in watercontaining excess sodium carbonate, the solution being kept alkaline bythe addition of more Na,CO as needed. The mixture is then filtered andthe filtrate is acidified. The precipitated product is filtered, driedand recrystallized from petroleum ether and ether to givel-cinnamylidene-2-methyl- 5-cyano-3-indenylacetic acid. F.l-Cinnamylidene-2-methyl-5-carboxamido-3 -indenylacetic acid The productof part E is stirred at room temperature with concentrated sulfuric aciduntil hydrolysis is substantially complete. The product is isolated bydrowning in water. It is I the above-named carboxamido compound. G.1-Cinnamylidene-2-methyl-5-carboxy-3-indenylacetic acid The product ofpart F is refluxed in 5 N NaOH until hydrolysis is substantiallycomplete. Acidification of the mixture precipitates the above-namedproduct. When this product is stirred at ambient temperature inmethanol, ethanol, propanol or butanol, in the presence of a smallamount of sulfuric acid,

the corresponding methyl, ethyl, propyl or butyl ester is formed, e.g.,l-cinnamylidene-2-methyl-5-carbo-methoxy-3- indenylacetic acid methylester.

EXAMPLE 4l lCinnamylidene-2-methyl-5-methylthio-3-indenyl acetic acidThe procedure of example 1 is followed substitutingpmethylthiobenzaldehyde for p-anisaldehyde, to give ethyl-2- hydroxy-2-(p-methylthiophenyl l -methylpropionate and from this6-methylthio-2-methylindanone. This product is then used in theprocedure of example 2 to give ethyl-5-methylthio-2-methyl-3-indenylacetate, which, when used in the procedureof example 8, gives l-cinnamylidene-2-methyl-5-methylthio-3-indenylacetic acid.

When, in the above procedure, 4-methylsulfonylbenzaldehyde,4-dimethylsulfamylbenzaldehyde, 4- dimethylaminoethylbenzaldehyde,4-phenylsulfonylbenzaldehyde, 4-benzyloxybenzaldehyde,4-phenoxybenzaldehyde dried and evaporated to yield the S-allyloxycompound.

When cyclopentylbromide is used in place of the allylbromide, thecorresponding 5-cyclopentyloxy compound is obtained.

EXAMPLE 43 l-Cinnamylidene-2-methyl-5-vinyl-3-indenylacetic acid Amixture of l-cinnamylidene-2-methyl-5-dimethylaminoethyl-3-indenylacetic acid (example 41 molar excess ofmethyliodiode and ethanol is heated until quaternization is complete.Evaporation, to dryness in vacuo yields the residue consisting of thetrimethylammonium ethyl iodide salt. This salt is then dissolved in 2NNaOH and the mixture is heated 4 hours on a steam-bath. The mixture isthen cooled and acidified. The precipitated 1-cinnamylidene-Z-methyl-S-vinyl-3-indenylacetic acid is filtered and dried.

We claim:

I. A compound of the formula:

(EHCOM in which:

R is loweralkylsulfinyl or loweralkylsulfonyl; X is an alkylene oralkenylene group having 2 carbon atoms; R, is loweralkyl; R is hydrogenor loweralkyl; R is loweralkyl, loweralkoxy, diloweralkylamino, halogenor halogenoalkyl; R, and R are hydrogen or any of the groups defining Rand M is hydroxy or loweralkoxy. 2. a-(l-p-Methylsulfinylcinnamylidenyl-Z-methyI-S-fluoro- 3-indenyl)-aceticacid.

3. a-( l-p-Methylsulfinylcinnamylidenyl-2-methyl-5-fluoro- 3-indenyl)-propionic acid.

4. a-( l-p-Methylsulfonylcinnamylidenyl-2-methyl-5-fluoro-3-indenyl)-acetic acid.

5. a-( l-p-Methylsulfinylcinnamylidenyl-5-methoxy-6- fluoro-3-indenyl)-acetic acid.

l t i

2. Alpha-(1-p-Methylsulfinylcinnamylidenyl-2-methyl-5-fluoro-3-indenyl)-aceticacid.
 3. Alpha-(1-p-Methylsulfinylcinnamylidenyl-2-methyl-5-fluoro-3-indenyl)-propionicacid.
 4. Alpha-(1-p-Methylsulfonylcinnamylidenyl-2-methyl-5-fluoro-3-indenyl)-aceticacid.
 5. Alpha-(1-p-Methylsulfinylcinnamylidenyl-5-methoxy-6-fluoro-3-indenyl)-aceticacid.